1. Field of the Invention
The present invention generally relates to diagnostic and prognostic tests for disease progression. More particularly, it relates to a prognostic test for the stage of progression of HIV infected patients and a method for treating HIV infected patients based on the prognosis.
2. Description of the Related Art
Following immune activation, HIV-1-infected CD4+ cells synthesize viral proteins and release virions (Zagury et al, 1986). In infected cells, the regulatory transactivating-transcription protein tat, which is not found in the viral particle, but is encoded by the HIV-1 genome, enhances the transcription of viral mRNA through interaction with the cis-acting RNA sequence termed TAR (Cullen, 1991). In contrast to its enhancing effect on viral replication, tat impairs the normal physiologic machinery of infected T cells, thus contributing to their premature death (Zagury et al, 1986). The tat-induced cellular alterations may also be exercised in uninfected T cells, since this protein, released from acutely infected cells into the extracellular compartment (Ensoli et al, 1993), can target uninfected cells by a mechanism involving interaction with integrins (Hynes, 1992) or other cell membrane receptors (Weeks et al, 1993). Immune cells, which carry a large density of integrin receptors, particularly after activation (Hynes, 1987), may be dysregulated by extracellular tat, as shown in vitro (Zagury et al, 1996). Pretreatment of activated PBMCs with tat induces both T cell immune suppression (Viscidi et al, 1995; Chirmule et al, 1995) and apoptosis (Li et al, 1995; Westendorp et al, 1995; Katsikis et al, 1997). Extracellular tat acts not only on T cells but also on antigen processing cells (APCs), e.g., monocytes, macrophages and dendritic cells (Zagury et al, 1998). The tat-induced immunosuppressive effect is further promulgated by the enhanced secretion of the immunosuppressive cytokine, IFNα, by APCs (Zagury et al, 1998). The present inventors showed that PHA-activated PBMC cultures treated with HIV-1, but not untreated cultures, generate CD8+ suppressive T cells. In this in vitro experimental model, the potent role of tat and IFNα in HIV-1-induced immune-suppression was confirmed since specific anti-tat and anti-IFNα, but not control antibodies prevented the generation of CD8+ suppressive T cells (Zagury et al, 1998).
Currently, the prognostic indicator or marker is viral load. However, the work of the present inventors shows that it is not a good prognostic indicator of future disease progression at an early stage of disease when the viral-load remains low, but is merely an indicator of the stage of disease (asymptomatic versus sick). While a test for the viral p24 protein is commercially available, this test is only used to determine whether an individual is infected, and not as a prognostic indicator/marker of disease progression.
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